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| United States Patent |
5,069,908
|
|
Henley
|
December 3, 1991
|
Crosslinked hydrogel and method for making same
Abstract
A chemically crosslinked hydrogel includes an active ingredient for
transdermal transport selected from the group of lidocainehydrochloride,
hydrocortisone, menthol, and methyl salicylate and utilizes as a
crosslinking agent an aluminum acetate, which is a polyvalent salt, which
renders the resulting hydrogel electrically conductive with a resistance
of less than 10,000 ohms per linear centimeter.
| Inventors:
|
Henley; Ernest J. (Houston, TX)
|
| Assignee:
|
Henley International, Inc. (Sugar Land, TX)
|
| Appl. No.:
|
533805 |
| Filed:
|
June 6, 1990 |
| Current U.S. Class: |
424/449; 424/482; 424/485 |
| Intern'l Class: |
A61F 013/00 |
| Field of Search: |
424/443,448,449,484,485,486
|
References Cited
U.S. Patent Documents
| 4349470 | Sep., 1982 | Battista | 527/202.
|
| 4853227 | Aug., 1989 | Kurihara-Bergstrom | 424/443.
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: Horne; Leon R.
Attorney, Agent or Firm: Jennings, Carter, Thompson & Veal
Parent Case Text
This is a continuation-in-part of application Ser. No. 367,783 filed on
June 19, 1989, now abandoned.
Claims
What I claim is:
1. A crosslinked hydrogel for use in transcutaneous electrical nerve
stimulation and iontophoresis to provide transdermal delivery of an active
ingredient comprising:
(a) an active ingredient selected from the class of lidocainehydrochloride,
hydrocortisone, menthol or methyl salicylate;
(b) a crosslinking agent, aluminum acetate in a quantity of about 0.1% to
about 0.5% by weight to provide ionic conductivity in said hydrogel;
(c) water;
(d) an emulsifier selected from the class of propyleneglycol, lanolin,
stearic acid or ethyl alcohol; and
(e) carboxymethylcellulose in an amount of between 1.1% to 1.7% by weight,
wherein said hydrogel is characterized by having an electrical resistance
of less than 10,000 ohms per linear centimeter.
2. A crosslinked hydrogel as defined in claim 1 wherein said hydrogel
contains less than about 4% by weight lidocainehydrochloride as an active
ingredient.
3. A crosslinked hydrogel as defined in claim 1 containing up to 0.5%
hydrocortisone by weight as the active ingredient.
4. A crosslinked hydrogel as defined in claim 3 containing from about 0.0%
to about 2.0% menthol.
5. A crosslinked hydrogel as defined in claim 1 further comprising a scrim
supporting said gel in a predetermined shape.
6. A crosslinked hydrogen containing an active ingredient for transdermal
medical application comprising:
(a) water;
(b) an active ingredient selected from the class of menthol, methyl
salicylate, lidocainehydrochloride or hydrocortisone;
(c) aluminum acetate, a crosslinking agent providing ionic conductivity to
said hydrogel, in a quantity of about 0.1% to about 0.5% by weight such
that hydrogel has a resistance of less than 10,000 ohms per linear
centimeter; and
(d) carboxymethylcellulose in an amount of between about 1.1% to 1.7% by
weight.
7. A crosslinked hydrogel as defined in claim 6 containing from about 3% to
about 8% by weight methyl salicylate.
8. A crosslinked hydrogel as defined in claim 6 containing up to about 1.0%
by weight hydrocortisone.
9. A crosslinked hydrogel as defined in claim 6 containing up to about 4%
lidocainehydrochloride.
10. A crosslinked hydrogel as defined in claim 6 containing between 1.4 g
and 1.7 g of carboxymethylcellulose.
Description
FIELD OF THE INVENTION
The present invention relates to the field of conductive gels used for
transdermal drug application and more particularly to chemically
crosslinked hydrogels which retain an active ingredient in prolonged
contact with the skin for enhanced drug applications such as are
associated with TENS treatment, iontophoresis, and phonophoresis.
BACKGROUND OF THE INVENTION
Topical application of medication in the form of dermally applied cremes is
commonplace. Numerous non-prescription products containing methyl
salicylate, hydrocortisone, lidocainehydrochloride, or benzocaine may be
purchased off the shelf at any drug store. In these cremes, the active
ingredient is mixed with water and assorted high molecular weight waxes
and emulsifiers, such as propylene glycol, lanolin, stearic acid, and
ethyl alcohol, to form a creme which can be rubbed into the skin. Also
known are iontophoresis, the introduction of various ions through the skin
by electricity, and phonophoresis which is the transdermal introduction of
substance into the body by means of ultrasound. However, iontophoresis has
always used sponges or the like soaked in medicated water to provide the
source of the transfer medicants whereas phonophoresis has used cremes.
Hydrogels are also well known and have been used in conjunction with
medical electrodes. U.S. Pat. No. 4,706,680 issued Nov. 17, 1987 lists
numerous patents which disclose hydrophilic gels and medical electrodes
employing them. However, none of these patents appear to be directed to a
chemically crosslinked hydrogel wherein the crosslinking agent also is the
electrical conductivity agent.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a chemically crosslinked
hydrogel which would act as a carrier for a medicant to be applied
transdermally over a long period of time.
Another object of the invention is to provide a chemically crosslinked
hydrogel which contains an active ingredient susceptible to transfer in
iontophoresis and phonophoresis.
A further object of the invention is to provide a medicated electrode for
TENS application using biphasic waveforms.
For both iontophoresis and TENS application, the gels must be highly
conductive. Traditionally monovalent salts such as sodium chloride or
magnesium acetate have been added to the media so that electrical
resistance is lowered below 10,000 ohms per linear centimeter. In the
present invention, I have determined aluminum acetate, which is a
polyvalent salt, can be used to both crosslink a hydrogel and to render
the gel sufficiently conductive to be suitable for TENS or iontophoresis
applications. It is desirable to use crosslinked hydrogels as the media
because crosslinked hydrogels do not melt, thus the gel containing the
active ingredient can be affixed to the skin of a patient using an
adhesive tape and left on for an extended period of time. Over a period of
time, the water in the gel will slowly evaporate. For example, a
one-sixteenth inch thick hydrogel would dry in about 24 hours. The active
ingredient or medicant is absorbed into the body by transdermal transport.
Of course, a much more rapid absorption would be expected if the medicated
hydrogel were used with an iontophoresis electrode or was the media for
phonophoresis. Of course, the biphasic waveforms of the TENS application
do not lend themselves to iontophoresis, thus although TENS may not
increase the absorption rate, it will be appreciated that the TENS
electrode may be worn over an extended period of time during which the
therapy is intermittently applied. Thus, by medicating the electrodes in a
manner that facilitates wearing of the electrode and transdermal
transport, the patient receives continuous therapeutic and analgesic
benefits.
The therapeutic and analgesic benefits of the selected medicants are well
known, the medicants or active ingredients being lidocainehydrochloride,
menthol hydrocortisone, and methyl salicylate, each of which are commonly
used for such purposes. Because of various incompatibilities, there are
some differences in the formulation of each hydrogel, however each
contains the aluminum acetate as the crosslinking agent.
BRIEF DESCRIPTION OF THE DRAWINGS
Apparatus embodying features of my invention are depicted in the attached
figures which form a portion of this invention and wherein:
FIG. 1 is a perspective view of my crosslinked hydrogel with a peelable
release paper on each side;
FIG. 2 is a sectional view of the embodiment of FIG. 1;
FIG. 3 is a perspective view partially in section of my crosslinked
hydrogel with an internal scrim and peelable release paper on either side;
FIG. 4 is a sectional view of the embodiment of FIG. 3;
FIG. 5 is a perspective view of my hydrogel in conjunction with a treatment
device; and
FIG. 6 is a sectional view of the embodiment of FIG. 5.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to the Figures for a better understanding of the invention, it
will be appreciated that a chemically crosslinked hydrogel will remain
solid and in gel form as long as the water content is retained, therefore
it is desirable to enclose the hydrogel 11 within a removable container
such as a peelable release paper 12 as shown in FIGS. 1 and 2. It will be
appreciated that the hydrogel 11 can be formed and packaged in this manner
by conventional methods such as passing the plastic hydrogel 11 through a
set of forming rollers with strips of release paper 12 on either side.
Likewise the gel can be cured in molds of various shapes and sizes and
individually packaged. The crosslinked hydrogels 11 thus formed and in
accordance with my invention include a medicant as an active ingredient
which when placed into contact with the skin of a patient will be received
into the patient's system via transdermal transport. The preferred active
ingredients are lidocainehydrochloride, hydrocortisone, menthol, and
methyl salicylate, although other well-known ingredients used in topical
applications may be useful.
In FIGS. 3 and 4, the hydrogel is formed with a scrim 13 contained
internally, the scrim 13 may be gauze or a paper towel and serves to
strengthen the hydrogel.
In each of my hydrogels, I have utilized aluminum acetate as the
crosslinking and ionization agent, however each active ingredient requires
a somewhat different formulation as shown in the tables below. It should
be understood that is is difficult to achieve the desired stabilization of
the hydrogels in that if they are excessively crosslinked, the product
tends to decompose, while under-crosslinking leaves the product too fluid.
TABLE I
______________________________________
Lidocainehydrochloride Formulation #1
______________________________________
100 cc Water
1.4 g Carboxymethylcellulose
2.0 g Lidocainehydrochloride
7.2 g Gelatin
3.0 g Polyethylene glycol
0.17 g Aluminum acetate
______________________________________
TABLE II
______________________________________
Lidocainehydrochloride Formulation #2
______________________________________
100 cc Water
1.4 g Carboxymethylcellulose
2.0 g Lidocainehydrochloride
3.0 g Polyethylene glycol
0.7 g Menthol
0.17 g Aluminum acetate
______________________________________
TABLE III
______________________________________
Limits on Lidocainehydrochloride Formulation/
100 cc Water
______________________________________
1.2 to 1.7 g Carboxymethylcellulose
up to 4.0 g Lidocainehydrochloride
0.0 to 8.0 g Gelatin
0.0 to 6.0 g Polyethylene glycol
0.0 to 2.0 g Menthol
0.17 to 0.50
g Aluminum acetate
______________________________________
TABLE IV
______________________________________
Hydrocortisone Formulation
______________________________________
100 cc Water
1.4 g Carboxymethylcellulose
0.5 g Hydrocortisone
3.2 g Polyethylene glycol
1.0 g Menthol
0.16 g Lanolin
0.17 g Aluminum acetate
______________________________________
TABLE V
______________________________________
Limits on Hydrocortisone Formulation/
100 cc Water
______________________________________
1.1 to 1.6 g Carboxymethylcellulose
up to 0.5 g Hydrocortisone
2.0 to 5.0 g Polyethylene glycol
0.0 to 5.0 g Menthol
0.0 to 1.0 g Lanolin
0.17 to 0.50
g Aluminum acetate
______________________________________
TABLE VI
______________________________________
Methyl Salicylate Formulation
______________________________________
100 g Water
1.4 g Carboxymethycellulose
6.67 g Methyl salicylate
1.32 g Menthol
2.7 g Polyethylene glycol
0.14 g Lanolin
0.2 g Aluminum acetate
______________________________________
TABLE VII
______________________________________
Limits on Methyl Salicylate Formulation/
100 cc Water
______________________________________
1.2 to 1.6 g Carboxymethylcellulose
3.0 to 8.0 g Methyl salicylate
0.5 to 5.0 g Menthol
2.0 to 3.5 g Polyethylene glycol
0.0 to 2.2 g Lanolin
0.20 to 0.50
g Aluminum acetate
______________________________________
As may be seen from the tables, the chemicals used in each formulation are
readily commercially available from a variety of sources.
To produce any one of the formulations all of the ingredients listed in the
specific tables, e.g. Table IV, except the crosslinking agent, aluminum
acetate, are mixed at once and heated at about 160 degrees Fahrenheit for
one hour. The solution is then cooled to below 120 degrees, whereupon the
required amount of aluminum acetate is added. The solution may then be
fabricated into any of the products shown in FIGS. 1-6. For example, solid
discs, rectangles or squares may be made by pouring the solution into
appropriately shaped molds to the desired thickness. Electrodes, such as
shown in FIGS. 5 and 6, may be made by spraying or painting the solution
on a conductive carbon or silicon electrode 14 which can provide
electrical connection for TENS or iontophoresis treatment. Or the hydrogel
may be painted or sprayed onto a scrim 13, or fed through rollers together
with the release paper and scrim, which permits the fabrication of thinner
hydrogels due to the structural support of the scrim. The curing time for
crosslinking of the hydrogel is from about four to about twenty-four hours
at room temperature.
While I have shown my invention in various forms, it will be obvious to
those skilled in the art that it is not so limited but is susceptible of
various changes and modifications without departing from the spirit
thereof.
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